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Fly LMBR1/LIMR-Type Protein Lilipod Promotes Germ-Line Stem Cell Self-Renewal by Enhancing BMP Signaling

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Fly LMBR1/LIMR-Type Protein Lilipod Promotes Germ-Line Stem Cell Self-Renewal by Enhancing BMP Signaling Fly LMBR1/LIMR-type protein Lilipod promotes germ-line stem cell self-renewal by enhancing BMP signaling Darin Dolezala,1, Zhiyan Liub,1, Qingxiang Zhoub, and Francesca Pignonia,b,c,2 aDepartment of Biochemistry and Molecular Biology, Upstate Medical University, Syracuse, NY 13210; bDepartment of Ophthalmology and Center for Vision Research, Upstate Medical University, Syracuse, NY 13210; and cDepartment of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY 13210 Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved October 6, 2015 (received for review May 19, 2015) Limb development membrane protein-1 (LMBR1)/lipocalin-interact- cell remains in contact with the CCs and maintains stem cell ing membrane receptor (LIMR)-type proteins are putative nine- identity, whereas the other forms away from the niche and turns transmembrane receptors that are evolutionarily conserved across into a differentiating cystoblast (CB), the progenitor of egg cham- metazoans. However, their biological function is unknown. Here, we bers and ultimately oocytes. show that the fly family member Lilipod (Lili) is required for germ- The maintenance of ovarian stem cells is tightly regulated by line stem cell (GSC) self-renewal in the Drosophila ovary where it multiple extrinsic and intrinsic factors. Some of these factors re- enhances bone morphogenetic protein (BMP) signaling. lili mutant press the differentiation program in the renewed GSC, whereas GSCs are lost through differentiation, and display reduced levels of others relieve this repression in the CB. The major signaling sys- the Dpp transducer pMad and precocious activation of the master tem in this process is the BMP pathway (6). Specifically, the differentiation factor bam. Conversely, overexpressed Lili induces BMP2/4 ligand decapentaplegic (Dpp) is secreted by CCs and supernumerary pMad-positive bamP-GFP–negative GSCs. Interest- signals onto adjacent GSCs to prevent their differentiation. In the ingly, differentiation of lili mutant GSCs is bam-dependent; however, GSC, the signal is transmitted through the type I BMP receptor its effect on pMad is not. Thus, although it promotes stem cell thickveins (Tkv) and the receptor-regulated R-SMAD Mothers self-renewal by repressing a bam-dependent process, Lilipod en- against dpp (Mad) to the nucleus, thereby suppressing transcrip- hances transduction of the Dpp signal independently of its sup- tion of the differentiation-promoting factor Bag of marbles (Bam) (7, 8). Reduced BMP signaling favors differentiation resulting in pression of differentiation. In addition, because Lili is still required stem cell loss; conversely, increased BMP signaling favors self- by a ligand-independent BMP receptor, its function likely occurs renewal resulting in GSC hyperplasia. In this context, modulators between receptor activation and pMad phosphorylation within of signaling play a critical role in maintaining the optimal balance the signaling cascade. This first, to our knowledge, in vivo char- between self-renewal and differentiation. By enhancing BMP acterization of a LMBR1/LIMR-type protein in a genetic model re- pathway activity in one daughter cell and antagonizing it in the veals an important role in modulating BMP signaling during the other (9), they effect a dramatic switch from pathway on (in the asymmetric division of an adult stem cell population and in other renewed GSC) to pathway off (in the differentiating CB) during a BMP signaling contexts. single cell division. We present here the first evidence to our knowledge of a stem cell | germline | Dpp | decapentaplegic | lipocalin receptor physiological role for a LIMR/LMBR1-type protein in a model organism, showing that it contributes to the regulation of the he human lipocalin-interacting membrane receptor LIMR BMP pathway in the female germ line. CG5807 is required in T(also known as LMBR1L) and the closely related limb de- velopment membrane protein-1 (LMBR1) share a predicted mul- Significance titransmembrane (TM) structure that is strikingly different from other well-characterized integral membrane receptors. LIMR was Adult stem cells are maintained in an undifferentiated state in originally isolated by phage display through its interaction with response to factors provided by their surrounding niche micro- lipocalin-1 (Lcn-1), a secreted lipid-binding carrier protein (1). Cell environment. The Drosophila limb development membrane pro- culture studies showed that LIMR could mediate the internaliza- tein-1 (LMBR1)/lipocalin-interacting membrane receptor (LIMR) tion of Lcn-1, suggesting a role in cell signaling (2). However, be- type transmembrane protein Lilipod(Lili)isrequiredinovarian cause the physiological roles of both Lcn-1 and LIMR are unknown, germ-line stem cells (GSC) for their self-renewal. In the fly the significance of this observation is unclear. Less is known ovary, niche-secreted bone morphogenetic protein (BMP) ligands about the LMBR1 protein. Initially, the human locus was ge- activate signaling in the GSC to suppress transcription of the dif- netically linked to multiple congenital limb malformations. ferentiation factor Bam. Lili is required for this suppression and However, further studies of the human and mouse loci showed functions as a modulator of BMP signal transduction in this and that the original association with limb defects was incidental be- other contexts. LMBR1/LIMR type transmembrane proteins cause of the disruption of a long-range SHH enhancer located are conserved throughout the Metazoa, and this study pro- within an intron of LMBR1 (3). To date, no loss-of-function or vides the first example to our knowledge of physiological gain-of-function analyses of LIMR or LMBR1 have been reported function in a model organism. in any model system, and studies in vertebrates may be compli- cated by functional redundancy between the two family members. Author contributions: D.D., Z.L., and F.P. designed research; D.D., Z.L., and Q.Z. performed Drosophila contains a single uncharacterized LIMR-like pro- research; D.D. and Z.L. contributed new reagents/analytic tools; D.D., Z.L., Q.Z., and F.P. tein, CG5807, which is the shared ortholog of both LIMR and analyzed data; and D.D. and F.P. wrote the paper. LMBR1. We have investigated the fly gene in vivo and show here The authors declare no conflict of interest. that it functions in the germ-line stem cells (GSC) of the Dro- This article is a PNAS Direct Submission. sophila ovary. In the fruit fly, oocytes are continually produced by 1D.D. and Z.L. contributed equally to this work. GSCs that are housed within a structure called germarium (Fig. 2To whom correspondence should be addressed. Email: [email protected]. A 1 ); here, two to three GSCs adhere to cells of the somatic niche, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. thecapcells(CC)(4,5).AstheGSCsdivide,onedaughter 1073/pnas.1509856112/-/DCSupplemental. 13928–13933 | PNAS | November 10, 2015 | vol. 112 | no. 45 www.pnas.org/cgi/doi/10.1073/pnas.1509856112 Downloaded by guest on September 30, 2021 GSCs to promote BMP signaling and ensure the suppression of bam. Its loss leads to stem cell differentiation and sterility over time. Conversely, its overexpression increases the number of BMP-responsive cells, thereby expanding the GSC compartment. We also show that CG5807 affects the signaling cascade between the Tkv receptor and the Mad transducer, and that it operates in other BMP-signaling contexts in the soma. Based on these find- ings, we have named the CG5807 gene lilipod (lili) to reflect its sequence conservation and its function as a “LIMR-like promoter of ovarian dpp.” Results Lili Is Evolutionarily Conserved and Required in GSCs for Germ-Line Maintenance. The Lilipod protein shares 44% (71%) amino acid identity (similarity) with human LIMR and 43% (72%) identity (similarity) with human LMBR1 (Fig. S1). TMpred and TMHMM (v2.0) predict a structure with nine TM spanning regions, extra- cellular N- and intracellular C-termini, and a large 125-aa central loop (Fig. 1B), similar to that originally proposed for human LIMR 1 2 3 (2). Homozygous mutant animals (lili ,lili, or lili allele) died as young larvae (during L1 and early in L2), but could be rescued to WT viability by a genomic p(lili ) construct or by somatic expression A of Lili isoform A (hs-Gal4 or actin5C-Gal4 with UASt-lili ). lili expression is reported in several adult tissues with highest enrichment in the ovary and testis (flybase.org). To confirm ex- pression in the ovary, we used a liliP-eGFP reporter containing 626 bp of 5′-flanking genomic DNA (Fig. S2) and detected GFP protein in the GSCs and their progeny but not in the somatic niche (cap, escort, or terminal filament cells) (Fig. 1 C–C′′); at a later stage, expression is also found in the somatic follicular epithelium around the forming egg chambers (Fig. S3). Thus, lili is transcribed at least in the GSCs and the follicle cells. To investigate lili’s function in the germ line, we analyzed ho- mozygous mutant GSC clones induced in heterozygous females by the FLP/FRT method. Clonal GSCs and their progeny were iden- tified by loss of the constitutive β-galactosidase marker arm-lacZ and GSC maintenance was assessed at days 3, 10, and 17 after clonal induction (ACI). Control GSCs (wt) were maintained over time, with 75–85% of germaria still containing a clonal GSC at 17 d ACI (level at 3 d ACI set as 100%) (Fig. 1 D, E,andH and Dataset S1). By contrast, at 10 and 17 d ACI, the frequency of lili mutant GSCs had dropped drastically (Fig. 1 F–H and Dataset S1). As expected, mutant stem cell loss was generally accompanied by replacement with a wt stem cell (Fig. 1G). To confirm that this phenotype was due to loss of Lili, we rescued the stem cell loss by driving expression 2 lili A of the wt protein in lili mutant GSCs (i.e., mutant clones in a nos- Fig.
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